cardiovascular system 3

Pharmacology nifedipine Nifedipine was the first dihydropyridine derivative to be used clinically. Other dihydropyridines available for clinical use include nicardipine, isradipine, amlodipine, felodipine, and nimodipine. In contrast to the other calcium channel blockers, nimodipine is highly lipid soluble and penetrates the blood-brain barrier. It is indicated for vascular spasm after intracerebral bleeding. Nifedipine’s oral bioavailability is approximately 70%, with peak plasma levels occurring within 30 to 45 minutes. Protein binding is 95%, and elimination half-life is approximately 5 hours. Nifedipine is available for oral administration in capsular form.

The compound degenerates in the presence of light and moisture, preventing commercially available intravenous preparations. Puncture of the capsule and sublingual administration provide an onset of effects in 2 to 3 minutes. nicardipine Nicardipine is a dihydropyridine agent with a longer half-life than nifedipine and with vascular selectivity for coronary and cerebrovascular beds. Nicardipine may be the most potent overall relaxant of vascular smooth muscle among the dihydropyridines. Peak plasma levels are reached 1 hour after oral administration, with bioavailability of 35%. Plasma half-life is 8 to 9 hours. Although the drug undergoes extensive hepatic metabolism with less than 1% of the drug excreted renally, greater renal elimination occurs in some patients. Plasma levels may increase in patients with renal failure; reduction of the dose is recommended in these patients. Verapamil Verapamil’s structure is similar to that of papaverine. ]]

rapamil exhibits significant first-pass hepatic metabolism, with a bioavailability of only 10% to 20%. One hepatic metabolite, norverapamil, is active and has a potency approximately 20% of that of verapamil. Peak plasma levels are reached within 30 minutes. Bioavailability markedly increases in hepatic insufficiency, mandating reduced doses. Intravenous verapamil achieves hemodynamic and dromotropic effects within minutes, peaking at 15 minutes and lasting up to 6 hours. Accumulation of the drug occurs with prolonged half-life during long-term oral administration.

Diltiazem After oral dosing, the bioavailability of diltiazem is greater than that of verapamil, varying between 25% and 50%. Peak plasma concentration is achieved between 30 and 60 minutes, and elimination half-life is 2 to 6 hours. Protein binding is approximately 80%. As with verapamil, hepatic clearance is flow dependent and major hepatic metabolism occurs with metabolites having 40% of the clinical activity of diltiazem. Hepatic disease may require decreased dosing, whereas renal failure does not affect dosing. Significant Adverse Effects Most significant adverse hemodynamic effects can be predicted from the calcium channel blockers’ primary effects of vasodilation and negative inotropy, chronotropy, and dromotropy. Hypotension, heart failure, bradycardia and asystole, and AV nodal block have occurred with calcium channel blockers. These side effects are more likely to occur with combination therapy with β-blockers or digoxin, in the presence of hypokalemia.

Aldosterone Receptor Antagonists Aldosterone, a mineralocorticoid, is another important component of the neurohormonal hypothesis of heart failure. Although it was previously assumed that treatment with an ACE inhibitor (or ARB) would block the production of aldosterone in patients with heart failure, elevated levels of aldosterone have been measured despite inhibition of Ang II. Adverse effects of elevated aldosterone levels on the cardiovascular system include sodium retention, potassium and magnesium loss, ventricular remodeling (e.g., collagen production, myocyte growth, and hypertrophy), myo­cardial norepinephrine release, and endothelial dysfunction.

clinical evidence Two large-scale trials have demonstrated improved outcomes with aldosteronereceptor antagonism in chronic heart failure. The Randomized Aldactone Evaluation Study (RALES), conducted in more than 1600 symptomatic heart failure (e.g., stage C, NYHA III-IV) patients, showed the efficacy of spironolactone (26 mg/day) (in combination with standard therapy: ACE inhibitor, loop diuretic with or without digoxin and a β-blocker).

Eplerenone is a new aldosterone antagonist that lacks some of spironolactone’s common side effects. The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHSUS), conducted in more than 6600 patients with symptomatic heart failure within 3 to 14 days after myocardial infarction, showed that eplerenone (25 to 50 mg/day) in combination with ACE inhibitor, loop diuretic, and β-blocker reduced all-cause mortality (P = .008), death from cardiovascular causes (P = .0002), and hospitalization for cardiovascular event

β-Adrenergic Receptor Antagonists Sympathetic Nervous System Activation and Its Role in the Pathogenesis of Heart Failure Activation of the sympathetic nervous system (SNS) (e.g., after myocardial infarction or with long-standing hypertension), much like increases in RAS activity, contributes to the pathophysiology of heart failure. In brief, SNS activation leads to pathologic left ventricular growth and remodeling. Myocytes thicken and elongate, with eccentric hypertrophy and increases in sphericity. Wall stress is increased by this architecture, promoting subendocardial ischemia, cell death, and contractile dysfunction

. There is downregulation of calcium regulatory proteins, including sarcoplasmic reticulum calcium ATPase, and impairment of contractility and relaxation. The activated SNS can also be harmful to myocytes directly through programmed cell death. As myocytes are replaced by fibroblasts, the heart function deteriorates from this “remodeling.” The threshold for arrhythmias may also be lowered, contributing in a vicious, deteriorating cycle.

 How β-Adrenergic Receptor Blockers Influence the Pathophysiology of Heart Failure In chronic heart failure, the beneficial effects of long-term β-blockade include improved systolic function and myocardial energetics and reversal of pathologic remodeling. A shift in substrate utilization from free fatty acids to glucose, a more efficient fuel in the face of myocardial ischemia, may partly explain the improved energetics and mechanics in the failing heart treated with β-blockade. Heart rate, a major determinant of myocardial oxygen consumption, is reduced by β1-receptor blockade.